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Abstract

Mandatory vitamin B12 fortification of enriched grain products is long overdue in the United States and Canada. Fortification would help provide the 2.4 μg of synthetic vitamin B12 that the US Institute of Medicine recommends for all persons 50 years and older. The findings of Ray and colleagues1 in this issue suggest that B12 may also help to prevent neural tube defects. If recommendations for B12 fortification were followed, it is possible that cases of spina bifida and anencephaly would be prevented. Two hundred twenty thousand children each year acquire folic acid-preventable spina bifida because many governments, including all in Europe, have yet to implement mandatory folic acid fortification. Fortification with folic acid and vitamin B12 is safe and should be implemented in all countries.

Ray et al1 link indicators of vitamin B12 deficiency with neural tube defects, and suggest that consideration should be given to adding vitamin B12 to enriched grains. Such fortification with Vitamin B12 should in fact be required. The Institute of Medicine/Food Nutrition Board recommended in 1998 that persons 50 years and older should consume at least 2.4 μg of synthetic B12 daily.2 I suggested in 1997, and more recently with Brent,3 that there is ample justification to fortify flour with vitamin B12. Neither the FDA4 nor Canadian authorities have required vitamin B12, even though mandatory fortification of flour would likely be as successful as folic acid fortification. If B12 also helps to prevent birth defects, there is even more reason for B12 fortification.

The elephant in the living room, however, is not the absence of B12 in flour. It is rather that about 220,000 children around the globe each year continue to be born with folate-deficiency spina bifida and anencephaly. These babies are unnecessarily paralyzed or die prematurely because most governments have failed to require folic acid in centrally processed flours, or have failed to require enough (ie, the United States and Canada).5 We have known since the summer of 1991 that folic acid will prevent most cases of spina bifdia and anencephaly.6 No country in Europe has yet to require folic acid fortification. The behavior of the Dutch is the most difficult to understand. That government has refused to require folic acid fortification of flour. One consequence is that spina bifida is the main reason for childhood euthanasia in the Netherlands. The behavior of the English regulators is equally problematic. Their refusal to require mandatory folic acid fortification means that the taxpayers who paid for the study showing that folic acid will prevent birth defects have yet to reap the rewards of fortification.

Although an effective prevention for pediatric AIDS is rather rapidly implemented in developed countries, mandatory folic acid fortification has required years of discussion. The United States Public Health Service (PHS) took a year to recommend that all women capable of pregnancy should consume 400 μg of synthetic folic acid a day to prevent birth defects.7 It took the FDA (part of the PHS) more than 3 years to decide in 1996 to require folic acid fortification by January 1, 1998—7 1/2 years after the publication of the relevant study.8

The FDA reviewed much data, published proposed regulations for public review, and then issued the regulations. Does every country have to go through the same process? Much of the data are the same. It remains urgent for nutritional regulatory bodies to find a way to expedite regulations that will prevent spina bifida through folic acid fortification. Every day's delay results in children being born with unnecessary serious birth defects.

Procedural process is not the only problem with nutritional regulations. With folic acid, there has been unreasonable concern about safety. In making a decision to require a substance in the food, one should make a reasonable review of the safety issues. Unreasonable delays cause disability and early death.

Folic acid is not a new drug. It is a chemical that has been available since the 1950s, and has been used widely and safely to treat folate-deficiency diseases. Even 50,000 μg/day produces no signs of risk or toxicity. Before folic acid was added to flour, at least 20% of the US population had chronic exposures of at least 400 μg/day from multivitamins and breakfast cereals. The Harvard Nurses’ Study has provided substantial evidence of safety and even the possibility that folic acid prevents cardiovascular disease and colon cancer.9 Even so, regulators continue to raise new and old issues of safety that delay fortification.

It is unfortunate that the IOM report included a “tolerable upper level” for folic acid.2 Although folic acid is not toxic like vitamins A and D, toxicologists on the IOM committee unfortunately treated folic acid as being toxic. Even the IOM report noted that, if there were a risk from folic acid, it would be only among people consuming at least 5000 μg/day. The “evidence” for risk from 5000 μg/day derives from studies in the 1950s when persons who had pernicious anemia in remission from getting liver extract were deliberately removed from this successful therapy and placed on a therapy for at least 5000 μg of folic acid a day (which we now know is an ineffective therapy for pernicious anemia).10 When people are taken off vitamin B12, their pernicious anemia is now known to recur. In the studies in the 1950s, the patients without liver extract on folic acid became worse. It seems much more reasonable to conclude that the withdrawal of effective treatment caused the signs and symptoms of pernicious anemia rather than anything to do with folic acid. It is time to remove the tolerable upper level for folic acid.

If all this were not enough, there are new confusions arising. Recent discussion has centered on observations of “free” folic acid in humans, and to the supposed desirability of substituting synthetic 5 methyl tetrahydrofolate (5MTHF) for folic acid. The tone of current writing about “free” folic acid is that it is a new “risk” that regulators should discuss. Human exposure to free folic acid is not new. It is present in human serum when a bolus of 300 or more micrograms of folic acid is consumed. Most prenatal vitamins in the United States have had 800 or 1000 μg for at least 20 years, meaning that most fetuses and pregnant women have been exposed to free folic acid. Multivitamins in the United States also have had 400 μg for more than 20 years.

Merck is marketing 5 MTHF as “better” than folic acid because it is the “natural” form of folate. Putting aside the fact that we have little experience with human exposure to this synthetic folate, there are other reasons that it is inferior to folic acid. It is heat labile. It cannot be used to fortify flour, as its activity would be lost in cooking, although it could be used in supplements. As long as there is a tolerable upper level to worry regulators, putting 5 methyl in supplements would relieve worry as it cannot treat the anemia of B12 deficiency—the rationale for the tolerable upper limit. On the other hand, women of reproductive age with the B12 deficiencies described by Ray and colleagues may be harmed. In the presence of B12 deficiency, 5 MTHF will not produce tetrahydrofolate (THF), but folic acid will. Thus, women with B12 deficiency who consume folic acid supplements may have fewer babies with spina bifida than if they consumed supplements with 5 MTHF.

Finally, a new WHO manual on micronutrient fortification has issued recommendations that may be harmful. The US Institute of Medicine/Food Nutrition Board issued a recommendation for folate consumption at the population level that is lower than the recommendation for women of reproductive age. To prevent birth defects, it also recommended that all women of reproductive age consume 400 μg of synthetic folic acid in addition to eating a diet rich in natural folates. I learned in December at a meeting in Ukraine that WHO had decided not to consider the prevention of birth defects in its recommendation for consumption of folic acid from fortified foods. Rather, it would make recommendations based on the low level that is recommended for the general population. This is an error. Any country considering folic acid fortification should set concentrations that will result in as many women as possible consuming 400 μg of synthetic folic acid from fortified foods.

ABOUT THE AUTHOR

GODFREY OAKLEY is a research professor of epidemiology at the Rollins School of Public Health of Emory University, and the former Director of the Division of Birth Defects and Developmental Disabilities at CDC. He and his group at CDC were critical to marshalling the arguments that led FDA to require folic acid fortification in the United States. He continues to work to prevent spina bifida.

10. Vilter CF, Vilter RW, Spies TD. The treatment of pernicious and related anemias with synthetic folic acid: observations on maintenance of normal hematologic status and on occurrence of combined system disease at the end of one year. J Lab Clin Med. 1947;32:262–273.

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